The goal is to obtain preliminary data on omega-3 fatty acids (FA) effects on regional concentrations of total brain choline (tCho), total creatine (tCr) and 3-aminobutyric acid (GABA) - neurochemicals found to be abnormal in adolescent MDD, with proton magnetic resonance spectroscopic imaging (1H MRSI). A placebo-controlled trial of omega-3FA will address this goal. Rationale. The proposal rests on related findings that: 1) MDD emerges in adolescence;2) its pathophysiology involves abnormalities in fronto-striatal structures involving death and atrophy of glia and neurons;3) omega-3 FA play a crucial role in glial and neuronal function, are critical to the dynamic structures of neuronal membranes, and have promising therapeutic properties in MDD;4) omega-3FA effects on brain function can be assessed by 1H MRSI. Hypotheses are: in adolescents with MDD, 1) Compared to placebo, omega-3FA will lead to significantly lower concentrations of striatal (caudate and putamen) and anterior cingulate cortex (ACC) tCho, tCr, and greater GABA concentrations in the ACC;2) improvement with omega-3FA and placebo will be associated with decreases in striatal and ACC tCho and tCr, and increases in ACC GABA concentrations. Exploratorily, we will examine whether improvement with omega-3FA is more strongly associated with declines in striatal and ACC tCho and tCr, and increases in ACC GABA concentrations, than improvement with placebo. Methods. Subjects. Based on power analyses, 24 medically healthy, antidepressant-naive adolescents, ages 12-18, with MDD for at least 8 weeks and a severity score of >40 on the CDRS-R, and first MDD onset >12 years. MDD Diagnosis will be established with the K-SADS-PL. Study Treatments. 10 weeks of double-blind randomized treatment with omega-3FA (combined EPA/DHA, ratio 2:1) or matching placebo. Dose will be initiated at 1.2g/d, titrated flexibly every 2 weeks to 3.6g/d, maximum. Two weeks at each dose will inform clinical response at each dose. Assessments before and at study end include diagnosis, MDD severity (CDRS-R), and omega-3FA in red blood cells. Clinical global improvement, adverse events/vital signs, suicidal ideation, and food intake checklist will be obtained weekly. Neuroimaging will include multi-voxel 1H MRS acquired at high (3T) magnetic field with high spatial resolution, focusing on the striatum and the ACC, before and at the end of the 10 week trial. Adolescent MDD is a major public health concern, associated with morbidity and mortality. The proposed study represents the integration of advanced neuroimaging research and a rigorous clinical trial in adolescents with MDD. It seeks to lay the groundwork for translational approaches aimed at enhancing our understanding of the mechanisms of action of CAM's, and eventually may lead to novel and effective treatments for adolescent MDD. PUBLIC HEALTH RELAVANCE: This work seeks to lay the groundwork for translational approaches aimed at enhancing our understanding of the mechanisms of action of complementary and alternative medicines (CAM's) such as omega-3 fatty acids (FA). This study examines the effects of omega-3FA on brain chemicals in adolescents with major depressive disorder (MDD), a major public health concern. Laying the scientific groundwork for potentially important CAM's such as omega-3FA will accelerate their appropriate incorporation into standard medical practice (bedside to community translation) in specific disorders such as MDD.